The interplay between innate and adaptive immunity in the lung is central to the development of host response to infection and likely important in the development of many forms of lung disease including asthma, fibrosis, and lung transplant rejection. Inhalation of toxins commonly found in air pollution contributes to the development and progression of asthma and environmental airway injury. The overall goal of this research program is to identify genes that mediate the host response to a number of environmental toxins and allergens both in mouse models of environmental airway diseases and in human populations. Specific environmental challenges include lipopolysacharide (LPS), allergens (house dust mite and ovalbumin), ozone, and particulate matter. In the genetics of environmental asthma project, the goal is to identify genes that are involved in the development of airflow obstruction and airway inflammation in asthmatics, and to determine whether polymorphisms in these differentially expressed genes predispose individuals to develop asthma. Asthma is a complex genetic disorder that is caused by a number of unique gene-gene and gene-environment interactions. Inhaled environmental agents induce several very specific biologic responses in asthmatics, including the induction of acquired and innate immunity that leads to acute and chronic forms of airway inflammation and airway remodeling. Emerging evidence indicates that both acquired and innate immune responses in the lung may be influenced by polymorphic genes. In this project, we hypothesize that polymorphisms of genes expressed by airway cells in asthmatics following specific subsegmental airway challenges predispose individuals to the development of asthma. To test this hypothesis, we plan to identify the genes that are differentially expressed by cells in the airway epithelia following specific subsegmental airway challenge with stimuli that induce acquired (house dust mite) or innate (LPS) immune responses, and then determine whether polymorphisms in these genes are associated with the development of asthma in a separate, well characterized, familial cohort of asthmatics. In addition to subsegmental challenge studies in humans, we are investigating more closely the relationship between endotoxin exposure and allergic asthma in a mouse model of long term allergen exposure. In another line of investigation, we are using well-established mouse models of environmental airway disease to study the role of the Toll-like receptor 4 (TLR4) in the host response to specific environmental toxins. The lung is constantly exposed to a broad spectrum of environmental toxins, including microbiologic pathogens and their products, particulate matter, and ozone. A common feature of the host response to these toxins is both acute neutrophilic inflammation and upregulation of proinflammatory cytokines. Several lines of evidence demonstrate that TLR4 is required for innate immune responses to LPS from gram-negative bacteria but the role of TLR4 in the host response to other toxins such as ozone is at present unclear. Finally, we are examining the interplay between innate and adaptive immunity in the context of transplant biology. Chronic rejection manifest as airway fibrosis limit long?term survival after human lung transplant. Although rejection is thought to occur as a result of the recipient adaptive immune response to the allogenic lung tissue, the lung allograft is also exposed to significant innate immune stimuli in the form of inhalational toxins, infections, and other environmental stimuli. Our hypothesis in this line of investigation is that innate immune activation promotes the development of acute and chronic lung allograft rejection. In order to test this hypothesis we have isolated genetic material and tissue samples from over 200 lung transplant recipients and their respective donors and characterized their clinical outcomes with regards to graft rejection. We have also sought to develop a novel immunologically based murine transplant model of chronic lung rejection to pursue further testing of our hypothesis.